Hepatitis C Virus ("HCV") is an RNA virus which is responsible for approximately 75% of all cases of non-A, non-B hepatitis. Based upon epidemiologic and serologic surveys, it has been estimated that at least 1% to 2% of the world population is chronically infected with HCV (Davis et al., "Therapy for Chronic Hepatitis C" in Gastroenterology Clinics of North America, pp. 603-613, 1995). In the United States, approximately 150,000 acute cases occur annually, where it is the ninth leading cause of death. Moreover, approximately 50% of the acutely infected individuals go on to develop chronic liver disease, and of these, 25% will develop cirrhosis. In addition, on a worldwide basis, 50% of the cases of hepatocellular carcinoma are correlated with HCV infection.
HCV is a positive-stranded RNA virus that is related to the flaviviridae family. The virus, which was isolated and characterized in 1989 (Choo et al., Science 244:362-364, 1989) has an .about.9.5 Kb linear genome that replicates through a double stranded RNA intermediate, mediated by a virally encoded RNA-dependent RNA polymerase. There is no known DNA intermediate in the replication process. Presumably, because its replication is exclusively through RNA polymerases, which lack proofreading activities, variability in the coding sequences is a hallmark of individual HCV isolates.
At present, the only therapy which shows some promise for the treatment acute and chronic cases of HCV is alpha interferon (Fried and Hoofnagle, Seminars in Liver Disease 15(1):82-91, 1995). Treatment with alpha interferon however, particularly for chronic patients, produces only temporary results. In particular, in most studies where patients with chronic HCV infections are treated with alpha interferon, only 20% to 25% maintain a sustained, long-term response (Fried and Hoofnagle, supra). In addition, treatment with alpha interferon can produce a wide array of side effects, including systemic effects (e.g., fatigue, fever, headache, anorexia, weight loss, nausea, vomiting, diarrhea, and hair loss), neurologic and psychological effects, an increased susceptibility to infections, as well as an assortment of autoimmune diseases.
The present invention provides an effective treatment to combat HCV infection, and further provides other, related advantages.